EBioMedicine (Jun 2024)
Sialic acid blockade inhibits the metastatic spread of prostate cancer to boneResearch in context
- Kirsty Hodgson,
- Margarita Orozco-Moreno,
- Emily Archer Goode,
- Matthew Fisher,
- Rebecca Garnham,
- Richard Beatson,
- Helen Turner,
- Karen Livermore,
- Yuhan Zhou,
- Laura Wilson,
- Eline A. Visser,
- Johan FA. Pijnenborg,
- Nienke Eerden,
- Sam J. Moons,
- Emiel Rossing,
- Gerald Hysenaj,
- Rashi Krishna,
- Ziqian Peng,
- Kyla Putri Nangkana,
- Edward N. Schmidt,
- Adam Duxfield,
- Ella P. Dennis,
- Rakesh Heer,
- Michelle A. Lawson,
- Matthew Macauley,
- David J. Elliott,
- Christian Büll,
- Emma Scott,
- Thomas J. Boltje,
- Richard R. Drake,
- Ning Wang,
- Jennifer Munkley
Affiliations
- Kirsty Hodgson
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Margarita Orozco-Moreno
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Emily Archer Goode
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Matthew Fisher
- The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield, UK
- Rebecca Garnham
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Richard Beatson
- Centre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London (UCL), Rayne 9 Building, London WC1E 6JF, UK
- Helen Turner
- Cellular Pathology, The Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
- Karen Livermore
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Yuhan Zhou
- The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield, UK
- Laura Wilson
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, UK
- Eline A. Visser
- Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, the Netherlands
- Johan FA. Pijnenborg
- GlycoTherapeutics B.V., Nijmegen, the Netherlands
- Nienke Eerden
- Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, the Netherlands; GlycoTherapeutics B.V., Nijmegen, the Netherlands
- Sam J. Moons
- Synvenio B.V., Nijmegen, the Netherlands
- Emiel Rossing
- Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, the Netherlands
- Gerald Hysenaj
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Rashi Krishna
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Ziqian Peng
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Kyla Putri Nangkana
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Edward N. Schmidt
- Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Adam Duxfield
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK; International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK
- Ella P. Dennis
- International Centre for Life, Biosciences Institute, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK
- Rakesh Heer
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne NE2 4HH, UK; Department of Urology, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK
- Michelle A. Lawson
- The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield, UK
- Matthew Macauley
- Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- David J. Elliott
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Christian Büll
- Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, the Netherlands
- Emma Scott
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK
- Thomas J. Boltje
- Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, the Netherlands
- Richard R. Drake
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA
- Ning Wang
- The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield, UK; Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, LE2 7LX, UK; Corresponding author. The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield, UK.
- Jennifer Munkley
- Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle upon Tyne NE1 3BZ, UK; Corresponding author.
- Journal volume & issue
-
Vol. 104
p. 105163
Abstract
Summary: Background: Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression. Methods: Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis. Findings: ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone. Interpretation: Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer. Funding: Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.
